Effect of Visit-to-Visit Variation of Heart Rate and Systolic Blood Pressure on Outcomes in Chronic Systolic Heart Failure: Results From the Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial (SHIFT) Trial

Abstract

Background: Elevated resting heart rate (HR) and low systolic blood pressure (SBP) are related to poor outcomes in heart failure (HF). The association between visit-to-visit variation in SBP and HR and risk in HF is unknown.

Methods and results: In Systolic Heart Failure Treatment with the If inhibitor ivabradine Trial (SHIFT) patients, we evaluated relationships between mean HR, mean SBP, and visit-to-visit variations (coefficient of variation [CV]=SD/mean×100%) in SBP and HR (SBP-CV and HR-CV, respectively) and primary composite endpoint (cardiovascular mortality or HF hospitalization), its components, all-cause mortality, and all-cause hospitalization. High HR and low SBP were closely associated with risk for primary endpoint, all-cause mortality, and HF hospitalization. The highest number of primary endpoint events occurred in the highest HR tertile (38.8% vs 16.4% lowest tertile; P<0.001). For HR-CV, patients at highest risk were those in the lowest tertile. Patients in the lowest thirds of mean SBP and SBP-CV had the highest risk. The combination of high HR and low HR-CV had an additive deleterious effect on risk, as did that of low SBP and low SBP-CV. Ivabradine reduced mean HR and increased HR-CV, and increased SBP and SBP-CV slightly.

Conclusions: Beyond high HR and low SBP, low HR-CV and low SBP-CV are predictors of cardiovascular outcomes with additive effects on risk in HF, but with an unknown effect size. Beyond HR reduction, ivabradine increases HR-CV. Low visit-to-visit variation of HR and SBP might signal risk of cardiovascular outcomes in systolic HF.

Clinical trial registration: URL: http://www.isrctn.com/. Unique identifier: ISRCTN70429960.

Keywords: blood pressure; heart failure; heart rate–blood pressure variation.

© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1

Kaplan–Meier event curves for the primary endpoint (cardiovascular death or heart failure hospitalization) (A), heart failure hospitalization (B), and all‐cause mortality (C) in placebo (left) and ivabradine (right) patients according to thirds of mean rate (heart rate mean) tertiles. Cox regression P values are given. HR CV indicates coefficient of heart rate variation.

Figure 2

Kaplan–Meier event curves for the primary endpoint (cardiovascular death or heart failure hospitalization) (A), heart failure hospitalization (B), and all‐cause mortality (C) in placebo (left) and ivabradine (right) patients according to thirds of coefficient of heart rate variation (HR CV). Cox regression P values are given.

Figure 3

Adjusted hazard ratios show the association in placebo patients between thirds of heart rate (A, HR mean, left) and heart rate coefficient of variation (B, HR CV, right) and the primary endpoint (cardiovascular death or hospitalization for heart failure), cardiovascular mortality (CV mortality), heart failure hospitalization (HF hospitalization), all‐cause mortality, and all‐cause hospitalization.

Figure 4

Interaction between mean heart rate (HR mean) and heart rate coefficient of variation (HR CV) for the primary endpoint (cardiovascular death or heart failure hospitalization) (A), cardiovascular mortality (B), and heart failure hospitalization (C) in placebo (left) and ivabradine (right) patients.

Figure 5

Kaplan–Meier event curves for the primary endpoint (cardiovascular death or heart failure hospitalization) (A), heart failure hospitalization (B), and all‐cause mortality (C) in placebo (left) and ivabradine (right) patients according to thirds of mean systolic blood pressure (SBP mean).

Figure 6

Kaplan–Meier event curves for the primary endpoint (cardiovascular death or heart failure hospitalization) (A), heart failure hospitalization (B), and all‐cause mortality (C) in placebo (left) and ivabradine (right) patients according to thirds of coefficient of variation of systolic blood pressure (SBP CV). Cox regression P values are given.

Figure 7

Adjusted hazard ratios show the association in placebo patients between thirds of systolic blood pressure (A, SBP mean, left) and systolic blood pressure coefficient of variation (B, SBP CV, right) and the primary endpoint (cardiovascular death or hospitalization for heart failure), cardiovascular mortality (CV mortality), heart failure hospitalization (HF hospitalization), all‐cause mortality, and all‐cause hospitalization.

Figure 8

Interaction between mean systolic blood pressure (SBP mean) and systolic blood pressure coefficient of variation (SBP CV) for the primary endpoint (cardiovascular death or heart failure hospitalization) (A), cardiovascular mortality (B), and heart failure hospitalization (C) in placebo (left) and ivabradine (right) patients.

Figure 9

Kaplan–Meier event curves for the primary endpoint (cardiovascular death or heart failure hospitalization) (A), heart failure hospitalization (B), and all‐cause mortality (C) in placebo (left) and ivabradine (right) patients according to third of mean diastolic blood pressure (DBP). Cox regression P values are given.

Figure 10

Kaplan–Meier event curves for the primary endpoint (cardiovascular death or heart failure hospitalization) (A), heart failure hospitalization (B), and all‐cause mortality (C) in placebo (left) and ivabradine (right) patients according to third of diastolic blood pressure coefficient of variation (DBP CV). Cox regression P values are given.

Figure 11

Association in placebo patients between thirds of diastolic blood pressure (A, DBP mean, left) and diastolic blood pressure coefficient of variation (B, DBP CV, right) and the primary endpoint (cardiovascular death or hospitalization for heart failure), cardiovascular mortality (CV mortality), heart failure hospitalization (HF hospitalization), all‐cause mortality, and all‐cause hospitalization.

Figure 12

Interaction between mean heart rate (HR mean) and heart rate coefficient of variation (HR CV) for the primary endpoint (cardiovascular death or heart failure hospitalization) (A), cardiovascular mortality (B), and heart failure hospitalization (C) in placebo (left) and on ivabradine (right) patients.